ROCK1-directed basement membrane positioning coordinates epithelial tissue polarity

Daley, William P.; Gervais, Elise M.; Centanni, Samuel W.; Gulfo, Kathryn M.; Nelson, Deirdre A.; Larsen, Melinda

doi:10.1242/jcs.106567

Cited by 8 publications

(23 citation statements)

References 1 publication

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“…to cell growth inhibition, tumors established from the mouse xenograft experiment in our study exhibited stratified squamous differentiation with restored baso-apical tissue polarity in conjunction with production of the basement membrane, resembling normal esophageal epithelia. Our cDNA microarray analysis detected the upregulation of genes encoding basement membrane proteins (24), such as laminin and collagen type4, and also the upregulation of genes involved in cell/tissue polarity, such as BMP-4 (25), ZO-1 (26) and Rock-1 (27), which suggested that the molecular basis of miR-203 induced the restoration of tissue architecture in our model. Based on the concept that the interaction between the basement membrane and basal cells coordinates epithelial polarity (27)(28)(29), miR-203-induced molecular processes in basal cell subset of the tumor, possibly including cancer initiating cells, was suggested to play a key role in regulating the tumor organization in vivo.…”

Section: Discussionmentioning

confidence: 66%

“…In addition, based on the concept that the interaction between the basement membrane and basal cells coordinates epithelial polarity (27)(28)(29), miR-203-induced molecular processes in p75NTR-bright cells have been suggested to play a key role in regulating the architecture of tumor tissue. A more detailed investigation on the miR-203 target genes involved in the phenotypic change observed in our model may provide us with a better understanding of tumor tissue organization and also a novel target for therapy.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA-203 inhibits the progression of esophageal squamous cell carcinoma with restored epithelial tissue architecture in vivo

Okumura

Shimada

Moriyama

et al. 2014

International Journal of Oncology

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MicroRNA (miR)-203 has been shown to induce squamous differentiation of epidermal stem cells through the suppression of p63. The aim of this study was to assess the tumor suppressor effect of miR-203 in esophageal squamous cell carcinoma (ESCC) with focus on the regulation of the cell fate decisions and organization of tumor tissue architecture in vivo. Our investigation establishing stable clones from ESCC cell lines with induced miR-203 expression resulted in significant growth inhibition in a mouse xenograft model. Small foci were observed in xenograft tumors with stratified squamous differentiation in conjunction with restored baso-apical polarity. The expression of the basement membrane protein laminine was localized at the center of the foci and the basal cell marker p75NTR was expressed in the innermost layer. The expression of ki67 and p63 was co-localized at the center layers, while involucrin was expressed in the outer layers. Flow cytometry revealed that the p75NTR-positive cells expressing p63 and Bmi1 were well maintained, while the expression of p63 was suppressed in the p75NTR-negative cells. Our cDNA microarray analysis demonstrated the upregulation of genes involved in regulating tissue architecture, such as BMP-4 and ZO-1 in the mir-203 transfectant. Investigation using surgically removed ESCC specimens revealed that the expression of miR-203 significantly correlated with a favorable prognosis. These results demonstrated that miR-203 regulated both basal and supra-basal cell components to induce differentiation with restored epithelial tissue architecture, leading to significant tumor growth inhibition in vivo. Those results suggest the use of miR-203 as a novel therapeutic and diagnostic target in patients with ESCC.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

MicroRNA-203 inhibits the progression of esophageal squamous cell carcinoma with restored epithelial tissue architecture in vivo

Okumura

Shimada

Moriyama

et al. 2014

International Journal of Oncology

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“…In the 3D gel culture (Fig. 1 A), the soft gel matrix not only serves as a supporting material for cell growth and exerts physical constraints on cell migration; the matrix also acts as a chemical cue that guides polarity orientation and lumen development (30,31). To provide chemical cues for cyst generation on the microdisks, the culture medium was supplemented with soluble ECM proteins (0.18 mg/mL Matrigel, primarily comprising laminin, collagen IV, and entactin) ( Fig.…”

Section: Generation and Polarity Characterization Of Probe-accessiblementioning

confidence: 99%

Mechanical Characterization of Microengineered Epithelial Cysts by Using Atomic Force Microscopy

Shen

Guan

Serien

et al. 2017

Biophysical Journal

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Most organs contain interconnected tubular tissues that are one-cell-thick, polarized epithelial monolayers enclosing a fluid-filled lumen. Such tissue organization plays crucial roles in developmental and normal physiology, and the proper functioning of these tissues depends on their regulation by complex biochemical perturbations and equally important, but poorly understood, mechanical perturbations. In this study, by combining micropatterning techniques and atomic force microscopy, we developed a simple in vitro experimental platform for characterizing the mechanical properties of the MDCK II cyst, the simplest model of lumen-enclosing epithelial monolayers. By using this platform, we estimated the elasticity of the cyst monolayer and showed that the presence of a luminal space influences cyst mechanics substantially, which could be attributed to polarization and tissue-level coordination. More interestingly, the results from force-relaxation experiments showed that the cysts also displayed tissue-level poroelastic characteristics that differed slightly from those of single cells. Our study provides the first quantitative findings, to our knowledge, on the tissue-level mechanics of well-polarized epithelial cysts and offers new insights into the interplay between cyst mechanics and cyst physiology. Moreover, our simple platform is a potentially useful tool for enhancing the current understanding of cyst mechanics in health and disease.

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“…Branching initiates at E12 as clefts, or invaginations, form in the primary bud. 7,8 Rapid and iterative rounds of cleft formation and proliferation of newly formed epithelial buds characterize the early branching morphogenesis stages (E11-E14). During late development (E15-E18), secretory units begin to form that consist of differentiating secretory acinar cells surrounded by a layer of differentiating stellate, contractile myoepithelial cells, which are embedded in and participate in the assembly of the surrounding basement membrane, a specialized form of extracellular matrix that provides structural support as well as outside-in signals.…”

Section: Introductionmentioning

confidence: 99%

Par-1b is required for morphogenesis and differentiation of myoepithelial cells during salivary gland development

et al. 2016

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The salivary epithelium initiates as a solid mass of epithelial cells that are organized into a primary bud that undergoes morphogenesis and differentiation to yield bilayered acini consisting of interior secretory acinar cells that are surrounded by contractile myoepithelial cells in mature salivary glands. How the primary bud transitions into acini has not been previously documented. We document here that the outer epithelial cells subsequently undergo a vertical compression as they express smooth muscle α-actin and differentiate into myoepithelial cells. The outermost layer of polarized epithelial cells assemble and organize the basal deposition of basement membrane, which requires basal positioning of the polarity protein, Par-1b. Whether Par-1b is required for the vertical compression and differentiation of the myoepithelial cells is unknown. Following manipulation of Par-1b in salivary gland organ explants, Par-1b-inhibited explants showed both a reduced vertical compression of differentiating myoepithelial cells and reduced levels of smooth muscle α-actin. Rac1 knockdown and inhibition of Rac GTPase function also inhibited branching morphogenesis. Since Rac regulates cellular morphology, we investigated a contribution for Rac in myoepithelial cell differentiation. Inhibition of Rac GTPase activity showed a similar reduction in vertical compression and smooth muscle α-actin levels while decreasing the levels of Par-1b protein and altering its basal localization in the outer cells. Inhibition of ROCK, which is required for basal positioning of Par-1b, resulted in mislocalization of Par-1b and loss of vertical cellular compression, but did not significantly alter levels of smooth muscle α-actin in these cells. Overexpression of Par-1b in the presence of Rac inhibition restored basement membrane protein levels and localization. Our results indicate that the basal localization of Par-1b in the outer epithelial cells is required for myoepithelial cell compression, and Par-1b is required for myoepithelial differentiation, regardless of its localization.

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ROCK1-directed basement membrane positioning coordinates epithelial tissue polarity

Cited by 8 publications

References 1 publication

MicroRNA-203 inhibits the progression of esophageal squamous cell carcinoma with restored epithelial tissue architecture in vivo

MicroRNA-203 inhibits the progression of esophageal squamous cell carcinoma with restored epithelial tissue architecture in vivo

Mechanical Characterization of Microengineered Epithelial Cysts by Using Atomic Force Microscopy

Par-1b is required for morphogenesis and differentiation of myoepithelial cells during salivary gland development

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